According to statistics, there are about 4 million patients suffering from Parkinson's disease (PD) throughout the world now, wherein about 1.5 million patients are in the United States. The main clinical manifestation of PD includes difficulty to walk, tremor, dyskinesia, rigidity, bradykinesia, and incapability of being in equilibrium. Any age of person may be affected with PD, and the average age of onset is 60 years old. About five to ten percent of the patients are young patients whose age of onset is 40 years old or less. About five to ten percent of the patients have positive family history, which means genes can play a certain role in the pathogenic mechanism of PD.
There is a phenomenon in the PD patients that a large number of cells secreting dopamine in brain are damaged or died, resulting in the related dyskinesia. Dopamine agonist is an important drug for treating Parkinson's disease, and can produce a neurotransmitter that is important for motor function by simulating the action of dopamine so as to ameliorate symptoms. Rotigotine was developed by Schwarz Biosciences in Germany for the auxiliary therapy of the early successive Parkinson's disease and later Parkinson's disease, commercialized under the trademark name of Neupro, and approved to come into the market by FDA on May, 2007. Neupro was the first transdermal patch for the treatment of Parkinson's disease. The clinical research showed that administering once daily could maintain a steady drug level in 24-hour via percutaneous permeation.
Generally, the synthesis of rotigotine comprises the steps of reduction-amination of 5-methoxy-2-tetralone with n-propylamine, salt resolution, acylation, reduction, demethylation, and salt purification, etc. (Drugs Fut, 1993, 18, (11):1005; J Chem Soc, 1965, 2636-41; U.S. Pat. No. 4,968,837). This synthetic route requires a plural of steps with a low yield. Especially, the steps of the acylation and the following reduction relate to a relatively complicated reaction, and may cause racemization of partial intermediates, resulting in a low yield of the whole synthetic route. Moreover, the reducing agent is expensive, which makes rotigotine quite expensive.
Ever since a long time ago, the synthetic process of rotigotine has being optimized. It is disclosed in U.S. Pat. No. 5,382,596, U.S. Pat. No. 4,410,519, U.S. Pat. No. 6,372,920 and WO2009/056791 that the product of the reduction-amination of 5-methoxy-2-tetralone with n-propylamine is directly subjected to an alkylation with 2-thienylethyl, instead of the previous acylation and reduction, wherein the alkylating agent is 2-thienylethane with a leaving group. The main differences among these alkylation methods are that the leaving group of 2-thienylethane and the optimization for operation are different.
It is a pity that all the yields of the above variously optimized processes are not satisfied, among them, the highest is only 55%. Moreover, the purification procedure requires using column chromatography. The overall efficiencies of the above processes are very low, although the starting materials can be recovered. In addition, all the above optimized processes are based on the alkylation following the introduction of a leaving group to 2-thienylethane, which increases the reaction procedures.